Clinical and immunologic responses to multiple doses of IMVAMUNE® (Modified Vaccinia Ankara) followed by Dryvax® challenge

Abstract

Smallpox vaccination with replication deficient vaccinia strains such as Modified Vaccinia-Ankara (MVA) may induce protective immunity with improved safety and tolerability profiles compared with currently available smallpox vaccines. Ninety subjects were randomized equally to 6 groups in a partially blinded, randomized control clinical trial. IMVAMUNE ® (MVA-BN ® , Bavarian Nordic A/S, Kvistgård, Denmark) vaccine or placebo was administered at Study Day 0 and 28 by subcutaneous or intramuscular injection and five groups were challenged with Dryvax ® at study Day 112. Vaccination with two doses of IMVAMUNE ® was safe and well-tolerated compared to Dryvax ® . IMVAMUNE ® produced comparable cellular and humoral immune responses to one dose of Dryvax ® and the immunity induced appears robust 90 days post vaccination by evidence of attenuated primary cutaneous reaction responses following Dryvax ® . IMVAMUNE ® vaccination prior to Dryvax ® reduced virus replication at the Dryvax ® site, decreased the size of the primary cutaneous lesion, and decreased the time to healing but did not completely ameliorate the immune response. MO 63110,, E-mail address: E-mail: freyse@slu.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In a recent study, IMVAMUNE ® , a highly attenuated vaccinia strain derived from MVA-572 (obtained from Dr. Anton Mahr), does not replicate in human cells and was safe and immunogenic in humans [9]. The present study sought to evaluate the safety and immunogenicity of a range of doses and routes of administration of IMVAMUNE ® . Potential surrogate efficacy of MVA-induced immune responses was evaluated by the ability of two doses of IMVAMUNE ® to reduce the clinical effects of a Dryvax ® challenge. Keywords NIH Public Access Author Manuscript Methods Vaccines and DiluentsIMVAMUNE ® (Bavarian Nordic A/S, Kvistgård, Denmark), a modified vaccinia Ankara vaccine (lot no. 130303), is a non-replicating virus in human cells used as the MVA smallpox vaccine in this study. Lyophilized vaccine was reconstituted with sterile water for injection (WFI) (Impfstoffwerk Dessau-Thornau GmbH, Germany). The reconstituted vaccine contains approximately 2 × 10 8 TCID 50 per ml. The placebo was sterile saline for injection (American Regent Laboratories, Inc, Shirley, NY). Licensed smallpox vaccine (Dryvax ® , Wyeth Laboratories, Marietta, PA) (lot no. 4008284), a replicating vaccinia virus provided by the Centers for Disease Control and Prevention in Atlanta, GA, was used as both the comparator vaccine and the virus in the challenge portion of this study.Reconstituted IM...

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“…Our results showed that two-dose IMVAMUNE (6.26 ϫ 10 2 ) induced a higher peak level of NAbs (with day 0 at 30 days after the second vaccination) than Dryvax (2.38 ϫ 10 2 ) or Acambis2000 (8.94 ϫ 10 1 ). This is consistent with previous reports that "first-generation" vaccines induce similar higher levels of anti-VACV NAbs than "second-generation" vaccines (22), and it recapitulates findings (17) where, in human volunteers, two doses of MVA generated higher levels of NAbs than Dryvax alone. Similarly, in MPXV-infected NHP (13) and RPXV-infected rabbit challenge models (18), a twodose MVA regimen elicited higher levels of NAbs than Dryvax.…”

“…2). Our results confirmed the boosting effect of the second dose of IMVAMUNE (17), as Abs induced with a single dose were 12.9-fold lower than the level induced by two doses.…”

“…In OPXV infections, examination of the effects and interactions of the humoral and cellular responses induced by smallpox vaccines is an active area of research (51,52,73). NAbs appear to be more necessary for protection from challenge than cellular responses (9,15,17,54,56), but there is compelling evidence that intramuscular administration of MVA protects B cell-deficient mice (79), indicating that MVA can protect irrespective of Abs. The level of protection attributed to each immune response component appears to be highly variable across animal models (51), as MVA-vaccinated macaques have been shown to have lower cellular immune responses than Dryvax-vaccinated macaques (54), but human MVA vaccinees have higher VACVspecific CD8 T cell responses (56).…”

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“…This vaccine is currently stockpiled in the United States for use during an emergency, such as an imminent bioterrorist attack, to protect individuals who are at risk of developing side effects from older vaccines (37). Studies have been published demonstrating the safety, immunogenicity (4), and protective efficacy against vaccinia virus scarification in humans (38) of Imvamune delivered in a single-or twodose regime. Several studies have also shown its protective potency in animals (33,39,40).…”